Early detection of Constitutional Mismatch Repair Deficiency cancer syndrome

18 October 2016

Dr Ian Carr, University of Leeds

Constitutional Mismatch Repair Deficiency is a rare inherited cancer syndrome. Most of those affected die in childhood. Early diagnosis is important but challenging. This project should result in the development of a new diagnostic test to aid early diagnosis and thus enable earlier clinical intervention.

Amount of grant: £31,587 | Date of award: July 2016

Background

Constitutional Mismatch Repair Deficiency (CMMRD) is a rare inherited cancer syndrome.

CMMRD is caused by inheriting defective genes that are important in the repair of damaged DNA. There are four genes that are known to cause CMMRD if defective. These genes are all important in repairing damaged DNA; without them the DNA becomes unstable as mutations accumulate. When mutations are not corrected this leads to the development of cancers.

Patients with CMMRD are typically children who can develop various cancers, including brain, blood and intestinal cancer. Most patients die in childhood.

Initial symptoms of CMMRD can be non-cancer changes such as altered pigmentation in small areas of skin. These symptoms are not specific to CMMRD but may be a result of other conditions. Therefore it can be difficult to diagnose CMMRD until additional symptoms present. As most CMMRD patients die in childhood, there is an urgent need to improve detection in order to provide treatment as early as possible.

Dr Carr has previously developed a simple test to detect defective repair in blood DNA. This test is now used diagnostically in patients suspected of having CMMRD. For technical reasons however, the test can only detect defects in three of the four genes associated with CMMRD. It does not detect defects in the fourth gene, MSH6, meaning that individuals with this particular defect go undetected. A different test needs to be developed for this patient group.

During this short project the team will develop a screening method for rapid identification of individuals with defective MSH6, investigating two different methods of identifying the defect. 

About the research team

The research team is very well suited and both qualified and experienced to carry out this project.
External reviewer
Dr Ian Carr is a Lecturer in Bioinformatics at the University of Leeds. He has extensive experience in the techniques and analysis required to carry out this work. The University’s DNA sequencing facility, which is headed by Dr Carr, has all the specialised equipment needed for this project.

Dr Carr is collaborating with Eamonn Sheridan, Professor Clinical Genetics at the University of Leeds and Consultant Clinical Geneticist at Leeds Teaching Hospital NHS Trust, providing access to the DNA samples required as well as Professor Sheridan’s expertise in managing this disease.

What difference will this project make?

Timely and definite diagnosis of this syndrome has important implications for the management not only of the patient but also the entire family.
External reviewer
Diagnosis of CMMRD is challenging but early diagnosis is vital if we are to improve outcomes for affected children.

Initial symptoms are often not specific to CMMRD, so it can be difficult to diagnose CMMRD until additional symptoms present. As most patients die in childhood, there is an urgent need to improve detection in order to provide clinical management, surveillance and treatment as early as possible.

Developing a test that could be used routinely to screen large numbers of individuals suspected of having CMMRD would allow earlier detection and diagnosis. Not only would it identify patients that already have cancer at an earlier stage of their disease but crucially, as the test detects changes in DNA from blood rather than relying on the presence of tumour DNA, it could identify CMMRD individuals before any cancer has developed.

Identification of CMMRD patients at an earlier stage of their disease, or before any cancer has developed will allow much earlier clinical intervention. Children will be better monitored and treatment provided at an earlier stage, allowing the treatment to be far more effective and so extending the lives of children with this condition.

Read more: About childhood cancer

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